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Abstract:

Solid pharmaceutical formulations are prepared using compositions
comprising orlistat and having average particle sizes less than about 250
μm.

Claims:

1. A pharmaceutical composition comprising an orlistat powder having an
average particle size less than about 250 μm.

2. The pharmaceutical composition of claim 1, wherein an orlistat powder
has an average particle size less than about 200 μm.

3. The pharmaceutical composition of claim 1, having a bulk density
between about 0.2 and about 0.6 g/ml.

4. The pharmaceutical composition of claim 1, having a tapped density
between about 0.3 and about 0.8 g/ml.

5. The pharmaceutical composition of claim 1, having an angle of repose
not more than about 40.

6. A solid pharmaceutical formulation comprising the composition of claim
1, having an average particle size less than about 250 μm.

7. A solid pharmaceutical formulation comprising the composition of claim
1, having an average particle size greater than about 2 μm.

8. The solid pharmaceutical formulation of claim 6, having a unit weight
within the limits of .+-.10% of an average weight of 20 units of the
formulation.

9. The solid pharmaceutical formulation of claim 6, having a moisture
content less than about 7% w/w.

10. A process for the preparation of a solid pharmaceutical formulation of
claim 6, comprising:a) mixing orlistat and at least one pharmaceutical
excipient; andb) compressing the mixture or filling the mixture into
capsules.

11. A pharmaceutical formulation comprising orlistat, wherein the
formulation has a delactone orlistat impurity concentration less than
about 2% by weight of a label orlistat content.

12. A pharmaceutical formulation comprising orlistat, wherein the
formulation has a concentration of total impurities less than about 4% by
weight of a label orlistat content.

Description:

[0001]The present invention relates to pharmaceutical compositions
comprising orlistat, including its salts, solvates, polymorphs, racemic
mixtures, enantiomers, and mixtures thereof. The invention also relates
to pharmaceutical formulations comprising compositions of orlistat or its
salts. Further the invention also relates to processes for preparation of
the compositions and formulations of orlistat, and their methods of use.

[0002]Tetrahydrolipstatin ("THL") is an inhibitor of pancreatic lipase and
is known under the officially adopted name "orlistat." Orlistat has a
chemical name (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecyl
ester and is structurally represented by (1).

##STR00001##

[0003]The empirical formula of the compound is C29H53NO.sub.5,
and its molecular weight is 495.7. It is a single diastereomeric molecule
that contains four chiral centers, with a negative optical rotation in
ethanol at 529 nm.

[0004]Orlistat is a white to off-white crystalline powder. Orlistat is
practically insoluble in water, freely soluble in chloroform, and very
soluble in methanol and ethanol. Orlistat has no pKa within the
physiological pH range.

[0005]Orlistat mainly acts by reducing the absorption of amount of fats
taken up by the patient, which leads to excretion of the unabsorbed fats
in the feaces. Reduction in the absorption of the fats leads to reduction
in body weight.

[0006]Orlistat is available in hard gelatin capsules in the two strengths
of 120 mg and 60 mg, respectively marketed as XENICAL® and ALLI®.

[0007]XENICAL and ALLI products are used in the treatment of obesity
management, including weight loss and weight maintenance, when used in
conjunction with a reduced-calorie diet. The products are also indicated
to reduce the risk for weight regain after prior weight loss.

[0009]Orlistat is a BCS (Biopharmaceutical Classification System) class II
compound and is insoluble in water. Orlistat is a waxy, fluffy and sticky
material having a low melting point about 44° C. Due to its nature
and low melting point, orlistat is prone to physical instability, and
also processing of orlistat into pharmaceutical formulations is
difficult.

[0010]To address the instability issues of orlistat, various methods have
been adopted. These methods have been observed to be tedious and costly.
Hence there is still a need for simple formulations, and simple processes
to prepare the formulations, which are cost-effective.

SUMMARY

[0011]The present invention relates to pharmaceutical compositions
comprising orlistat, including its salts, solvates, polymorphs, racemic
mixtures, enantiomers, and mixtures thereof. The invention also relates
to solid pharmaceutical formulations comprising compositions of orlistat
or its salts. Further the invention relates to processes for preparation
of the compositions and formulations of orlistat.

[0012]In an embodiment the invention includes pharmaceutical compositions
comprising orlistat having average particle sizes less than 250 μm, or
less than about 200 μm, or less than about 150 μm.

[0013]In embodiments, pharmaceutical compositions comprising orlistat and
at least one pharmaceutically acceptable excipient, wherein average
particle sizes of compositions is less than about 250 μm, or less than
about 200 μm, or less than about 150 μm

[0014]In another embodiment the invention includes pharmaceutical
compositions comprising orlistat and at least one pharmaceutically
acceptable excipient, wherein average particle sizes of the compositions
are more than about 2 mm.

[0015]In an embodiment, pharmaceutical formulations comprising
compositions of orlistat, wherein the average sizes of the compositions
is less than about 250 μm, or less than about 200 μm, or less than
about 150 μm.

[0016]In an embodiment, pharmaceutical formulations comprising
compositions of orlistat, wherein the average sizes of the compositions
are more than about 2 mm, or more than about 2.5 mm, or more than about 3
mm.

[0018]In an embodiment the invention includes pharmaceutical formulations
comprising orlistat, wherein the concentration of delactone orlistat
impurity is less than about 2%, or less than about 1.5%, by weight of a
label orlistat content.

[0019]Further embodiments of the invention include pharmaceutical
formulations comprising orlistat, wherein the concentration of total
impurities is less than about 4%, or less than about 2%, by weight of a
label orlistat content.

[0021]An embodiment of the present invention includes bulk densities and
tapped densities of orlistat or its salts which are in the range of about
0.2 g/ml to about 0.6 g/ml, and about 0.3 g/ml to about 0.8 g/ml,
respectively.

[0022]In an embodiment the present invention includes bulk densities and
tapped densities of final blends comprising orlistat and at least one
pharmaceutical excipient in the range of about 0.2 g/ml to about 0.6
g/ml, and about 0.3 g/ml to about 0.8 g/ml, respectively.

[0023]In an embodiment the present invention further includes methods of
using the pharmaceutical formulations in the treatment of obesity and
related disorders.

[0026]The numbers of people suffering from obesity have tremendously
increased in recent years. The prevalence of obesity increased not only
in adults but also, to a marked extent, in adolescents. Increases in
obesity lead to various disorders such as hypertension, cardiac failure
and diabetes mellitus.

[0027]Orlistat is a reversible lipase inhibitor. It exerts its therapeutic
activity in the lumen of the stomach and small intestine by forming
covalent bonds with active serine sites of gastric and pancreatic
lipases. The inactivated enzymes are thus unavailable to hydrolyze
dietary fat in the form of triglycerides into absorbable free fatty acids
and monoglycerides; undigested fats are not absorbed, and the resulting
caloric deficit may have a positive effect on weight control.

[0028]The term "average particle size" refers to particle sizes
represented by D(0.5), wherein 50% of particles in a powder have sizes
greater than, and 50% of particles have sizes less than, a specified
value.

[0029]The term "composition" refers to a mixture comprising orlistat and
at least one pharmaceutically acceptable excipient, wherein the
compositions can be in the form of powders, granules, pellets, particles,
or minitablets.

[0031]The term "stability" includes both physical and chemical stability,
suitable for commercial activities. This implies maintenance of original
formulation specifications after manufacture, for a period of at least
about six months, or at least about 1 year, or at least about 2 years, to
the extent necessary for sale and use of the formulation.

[0032]"Physical stability" is evidenced by maintenance of initial
formulation XRD patterns during storage and use.

[0035]Various parameters impacting the preparation of solid oral dosage
forms include the physical properties of active ingredients as well as
those of the final blends of active ingredients with excipients, wherein
the physical properties include flow properties, particle sizes (such as
determined by sieve analyzers, electrical conductance instruments such as
a Coulter counter, and laser light diffraction particle size analyzers
such as the instruments available from Malvern Instruments, Ltd.,
Malvern, Worcestershire, United Kingdom), bulk densities and tapped
densities, compressibility indexes, Hausner ratios (determined by USP
density apparatus), flow properties (such as determined by Flowdex
apparatus), etc.

[0036]Particle sizes play an important role in establishing solubility. As
the particle sizes are reduced, the surface areas of the individual
particles of orlistat increase, thus a greater amount of orlistat can be
solubilized for obtaining a therapeutic effect, which leads to higher
therapeutic efficacy.

[0037]The percent of particles with different dimensions that exist in a
powder is called the particle size distribution. It is represented in
certain ways. Particle size is the maximum dimension of a particle,
normally expressed in units of μm. Particle size distributions can be
expressed in terms of D(0.1), D(0.5), D(0.9) and D [4,3]. The D(0.1),
D(0.5) and D(0.9) represent the 10th, median or the 50th percentile, and
the 90th percentile of the particle size distribution, respectively. They
can be expressed as volume, weight, or surface percentages. For example
when measured by volume, D(0.1), D(0.5), D(0.9) is a value of the
distribution such that 10%, 50%, 90% by volume of the particles have a
size of this value or less, or is the percentage of particles smaller
than that size. D(0.5) is also known as median diameter of particle. It
is one of the important parameters representing characteristics of
particle of powder. For a sample, if D(0.5)=5 μm, it means that 50% of
the particles are smaller than 5 μm. Similarly, if D(0.1)=5 μm, 10%
by volume of the particles are less than or equal to 5 μm, and if
D(0.9)=5 μm, 90% of the particles are less than or equal to 5 μm.
D[4,3] is the volume moment mean of the particles or the volume weighted
particle size.

[0038]In an embodiment the invention includes pharmaceutical compositions
comprising orlistat having average particle sizes less than 250 μm, or
less than about 200 μm, or less than about 150 μm, or less than
about 100 μm.

[0039]In embodiments, pharmaceutical compositions comprise orlistat and at
least one pharmaceutically acceptable excipient, wherein average particle
sizes of compositions are less than about 250 μm, or less than about
200 μm, or less than about 150 μm, or less than about 100 μm.

[0040]In another embodiment the invention includes pharmaceutical
compositions comprising orlistat and at least one pharmaceutically
acceptable excipient, wherein average particle sizes of the compositions
are more than about 2 mm, or more than about 2.5 mm, or more than about 3
mm. Sizes up to about 6 mm will generally be useful.

[0041]In an embodiment, pharmaceutical formulations comprise compositions
of orlistat, wherein the average sizes of the compositions are less than
about 250 μm, or less than about 200 μm, or less than about 150
μm, or less than about 100 μm.

[0042]In an embodiment, pharmaceutical formulations comprise compositions
of orlistat, wherein the average sizes of the composition particles are
more than about 2 mm, or more than about 2.5 mm, or more than about 3 mm.
The particles generally will not be larger than about 6 mm.

[0043]Other important physicochemical characteristics of powders are the
density properties such as bulk and tapped density, weight variation and
flow properties such as angle of repose. Bulk density is the undisturbed
packing density of that substance and tapped bulk density relates to the
packing density after tapping a bed of substance until no change in the
packing density is seen. Bulk density and tapped density, can be
determined using compendial bulk density apparatus, such as the method
given in Test 616 "Bulk Density and Tapped Density," United States
Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville,
Md., 2005 ("USP"). Weight variation can be determined using the method
given in United States Pharmacopeia 29.

[0044]In an embodiment, the present invention provides untapped bulk
densities and tapped densities of orlistat or a salt, etc. thereof in the
range of about 0.2 g/ml to about 0.6 g/ml, and about 0.3 g/ml to about
0.8 g/ml, respectively.

[0045]In an embodiment of the present invention, untapped bulk densities
and tapped densities of final blends comprising orlistat or a salt, etc.
thereof and at least one pharmaceutical excipient are in the range of
about 0.2 g/ml to about 0.6 g/ml, and about 0.3 g/ml to about 0.8 g/ml,
respectively

[0046]The flowability of a composition is influenced by the particle size
distribution, electrostatic properties, particle shapes and
hygroscopicity. Addition of flow aids may smooth the surfaces of the
particles leading to improved flowability. Moisture binds particles and
hence decreases the flowability. The determination of flowability is
based upon ability of the powder to fall freely through a hole in a disc.
The smaller the hole through which the powder falls freely, the better is
the flowability. Flowdex apparatus can be used to measure flowability and
the angle of repose. The Flowdex apparatus consists of a cylinder with
interchangeable discs having holes of various diameters at the bottom.
The cylinder is filled with powder without packing and the diameters of
the holes are successively reduced until the powder will not flow
through. The Flowdex flowability rating can then be calculated by
dividing 1000 by the smallest hole diameter (in mm) through which the
powder will flow.

[0047]For angle of repose, after carefully overfilling the cylinder with
powder and measuring the height of the powder cone (h) and the radius of
the cylinder (r), the angle of repose (tan α) can be calculated as:

[0049]In an embodiment the invention includes pharmaceutical compositions
comprising orlistat or its salts wherein angle of repose is less than
about 40, or less than about 30.

[0050]In yet another embodiment the invention includes solid
pharmaceutical formulations comprising orlistat or its salts wherein
weight variation of units of the formulation is within the limits of
±7.5%, or ±10%, of an average weight of 20 units of the
formulation.

[0051]Preparation of Formulations is Influenced by Physicochemical
Properties of active ingredients and other important additives. Due to
the low melting point of orlistat at about 44° C., conventional
dosage forms, for example tablets and capsules, cannot be easily
formulated from powder mixtures due to picking and sticking problems
during tablet compression or encapsulation. Further, due to its nature,
orlistat undergoes both hydrolytic and thermal degradation. The processes
of preparing formulations may involve several operations such as milling,
sieving, wet or dry granulation, slugging, encapsulation, etc. Mechanical
energy produced in such operations can be imparted to materials being
processed. Often, this leads to melting, deformulation or inactivation of
the drug substance.

[0052]Due to the instability of orlistat, impurities may be generated
during processing to prepare pharmaceutical formulations or during
stability testing. Some of the impurities that have been identified for
orlistat are described below.

[0053]Orlistat can undergo hydrolytic degradation to form compounds
including:

[0069]In an embodiment the invention includes stable pharmaceutical
formulations comprising orlistat, wherein the concentration of delactone
orlistat impurity is less than about 2%, or less than about 1.5%, by
weight of a label orlistat content.

[0070]Further embodiments of the invention includes stable formulations
comprising orlistat, wherein total impurities are less than about 4%, or
less than about 2%, by weight of an initial orlistat content.

[0071]In an embodiment the invention relates to analytical methods for
analysis of impurities using high performance liquid chromatography
(HPLC), wherein a method comprises the following:

[0072]Buffer solution: 1 g of sodium perchlorate monohydrate was dissolved
in 1 L of water and pH was adjusted to 2.5 with dilute orthophosphoric
acid solution. The solution was filtered through a 0.45 μm filter.

[0086]Various useful fillers or diluents include but are not limited to
starches, lactose, mannitol (Pearlitol® SD200), cellulose derivatives,
confectioner's sugar and the like. Different grades of lactose include
but are not limited to lactose monohydrate, lactose DT (direct
tableting), lactose anhydrous, Flowlac® (available from Meggle
Products), Pharmatose® (available from DMV) and others. Different
grades of starches include but are not limited to maize starch, potato
starch, rice starch, wheat starch, pregelatinized starch (commercially
available as PCS PC10 from Signet Chemical Corporation) and Starch 1500,
Starch 1500 LM grade (low moisture content grade) from Colorcon, fully
pregelatinized starch (commercially available as National 78-1551 from
Essex Grain Products) and others. Different cellulose compounds that can
be used include crystalline celluloses and powdered celluloses. Examples
of crystalline cellulose products include but are not limited to
CEOLUS® KG801, Avicel® PH101, PH102, PH301, PH302 and PH-F20,
PH-112 microcrystalline cellulose PH114, and microcrystalline cellulose
PH112. Other useful diluents include but are not limited to
croscarmellose, sugar alcohols such as mannitol, sorbitol and xylitol,
calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and
tribasic calcium phosphate.

[0089]Coloring agents can be used to color code the formulation, for
example, to indicate the type and dosage of the therapeutic agent
therein. Suitable coloring agents include, without limitation, natural
and/or artificial materials such as FD&C coloring agents, natural juice
concentrates, pigments such as titanium oxide, silicon dioxide, iron
oxides, and zinc oxide, combinations thereof, and the like.

[0091]One or more glidant materials, which improve the flow of a powder
blend and minimize the dosage form weight variation, can be used. Useful
glidants include but are not limited to silicone dioxide, talc, and
combinations thereof.

[0110]j) filling a lubricated blend from i) into capsules, or
alternatively compressing into tablets and optionally filling tablets
into capsules.

[0111]Dosage forms prepared by a process can be subjected to in vitro
dissolution testing, such as according to Test 711 "Dissolution" in
United States Pharmacopeia 29, United States Pharmacopeial Convention,
Inc., Rockville, Md., 2005 to determine the extent and rate at which the
active substance is released from the dosage forms, and the content of
the active substance can be determined in solutions using techniques such
as high performance liquid chromatography.

[0112]In an embodiment the present invention includes use of packaging
materials such as containers and lids of high-density polyethylene
(HYPE), low-density polyethylene (LDPE) and or polypropylene or
polyethylene and/or glass, and blisters or strips composed of aluminum or
high-density polypropylene, polyvinyl chloride, polyvinylidene
dichloride, or aluminum/aluminum foil blisters or polyvinyl
chloride/polyethylene/polyvinylidene dichloride (PVC/PE/PVDC) film
packaging.

[0113]Certain specific aspects and embodiments of this invention are
described in further detail by the examples below, which examples are
provided only for purposes of illustration and are not intended to limit
the scope of the invention in any manner.

[0162]The capsules were packed in blister packages made of a polyvinyl
chloride/polyethylene/polyvinylidene dichloride laminated film and
aluminum foil as a backing, and blisters were stored at 30° C. and
75% relative humidity (RH) for 1 month. FIG. 1 is a comparison of powder
X-ray diffraction (XRD) patterns, using copper Kα-1 radiation, of
the orlistat ingredient (A), the capsule contents as originally prepared
(B), and the capsule contents after storage (C). A "placebo" formulation
was similarly prepared using the above ingredients, but omitting the
orlistat, and the XRD pattern of the capsule contents is also shown (P).
The XRD pattern of the formulation before storage matches that of the
stored formulation, showing polymorphic stability.

[0163]The contents of packaged capsules stored at 30° C. and 75%
RH, and 25° C. and 60% RH, for 2 months were tested for impurities
by HPLC and for moisture content. Commercially available XENICAL capsules
were stored at 30° C. and 75% RH and similarly analyzed. The data
are given below:

[0166]The capsules prepared were tested for variability of the fill
weight. During the process of testing weight variation, an intact capsule
was weighed, the contents were removed, and the empty capsule shell was
weighed. The difference in the two weights is the fill weight. The
procedure was repeated for an additional 19 capsules. The average,
minimum and maximum of these twenty values were taken into consideration.
The minimum (-) and maximum (+) deviations (from the average weight)
percentages were calculated by:

[0179]1) Orlistat was combined with a mixture of isopropyl alcohol and
methylene chloride and stirred to form a clear solution.

[0180]2) MCC 112 was loaded into a fluid bed coater and solution from step
1) was sprayed onto the MCC 112.

[0181]3) The material from step 2) was dried at an inlet temperature of 30
to 45° C. and bed temperature of 25 to 30° C. for about 1
hour, yielding a fine powder having the appearance of the original MCC
112.